Method of treating or preventing peripheral neuropathy with a highly selective norepinephrine reuptake inhibitor

ABSTRACT

Methods and compositions for treating humans suffering from, or preventing a human from suffering, a physiological or psychiatric disease disorder, or a condition where inhibiting reuptake of norepinephrine is a benefit are disclosed. The compositions comprise a compound having a pharmacological selectivity of serotonin (K i )/norepinephrine (K i ) of at least about 5000. Examples of such compounds include reboxetine, and more preferably optically pure (S,S) enantiomer of reboxetine. The methods generally include administration of a therapeutic amount of such compositions. Also disclosed are preparations of a medicament from the composition, and uses of the composition in a manufacture of the medicament to treat a human suffering from, or preventing a human from suffering, a physiological or psychiatric disease, disorder, or condition.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) ofU.S. provisional patent application Serial No. 60/141,968 filed Jul. 1,1999, U.S. provisional patent application Serial No. 60/144,131 filedJul. 16, 1999, U.S. provisional patent application Serial No. 60/158,256filed Oct. 6, 1999, and U.S. provisional patent application Serial No.60/170,381 filed Dec. 13, 1999, the disclosures of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to methods of treating individualssuffering from a variety of conditions wherein inhibiting reuptake ofnorepinephrine provides a benefit. In particular, the present inventionrelates to methods of treatment comprising administration of a compound,such as (S,S) reboxetine, to an individual, wherein the compound has ahigh pharmacological selectivity with respect to norepinephrine reuptakesites compared to serotonin reuptake sites. The present invention alsorelates to a composition containing the compound and to a preparation ofa medicament containing the composition.

[0004] 2. Brief Description of Related Technology

[0005] Many types of depression, mental, behavioral, and neurologicaldisorders originate from disturbances in brain circuits that conveysignals using certain monoamine neurotransmitters. Monoamineneurotransmitters include, for example, norepinephrine (noradrenaline),serotonin (5-HT), and dopamine. Lower-than-normal levels ofnorepinephrine are associated with a variety of symptoms including lackof energy, motivation, and interest in life, Thus, a normal level ofnorepinephrine is essential to maintaining drive and capacity forreward.

[0006] These neurotransmitters travel from the terminal of a neuronacross a small gap (i.e., the synaptic cleft) and bind to receptormolecules on the surface of a second neuron. This binding elicitsintracellular changes that initiate or activate a response or change inthe postsynaptic neuron. Inactivation occurs primarily by transport(i.e., reuptake) of the neurotransmitter back into the presynapticneuron. Abnormality in noradrenergic transmission results in varioustypes of depression, mental, behavioral, and neurological disordersattributed to a variety of symptoms including a lack of energy,motivation, and interest in life. See generally, R. J. Baldessarini,“Drugs and the Treatment of Psychiatric Disorders: Depression and Mania”in Goodnman and Gilman's The Pharmacological Basis of Therapeutics,McGraw-Hill, NY, N.Y., pp. 432-439 (1996).

[0007] Reboxetine (i.e., 2-[(2-ethoxyphenoxy)(phenyl)methyl]morpholine)raises the concentration of physiologically active norepinephrine bypreventing reuptake of norepinephrine, for example. Reboxetine is anorepinephrine reuptake inhibitor and has been shown to be effective inthe short-term (i.e., less than eight weeks) and long-term treatment ofdepression. In fact, reboxetine has been shown to have effectivenessthat is similar to fluoxetine, imipramine, and desipramine, commonlyprescribed antidepressants, in both adults and elderly patients. See S.A. Montgomery, Reboxetine: Additional Benefits to the Depressed Patient,Psychopharmocol (Oxf) 11:4 Suppl., S9-15 (Abstract) (1997).

[0008] Antidepressant drugs are sometimes divided into “generations.”Thefirst generation included the monoamine oxidase inhibitors (such asisocarboxazid and phenylhydrazine) and tricyclic agents (such asimipramine). The second generation of antidepressant drugs includedcompounds such as mianserin and trazodone. The third generation hasincluded drugs called selective reuptake inhibitors (e.g., fluoxetine,sertraline, paroxetine, and reboxetine). Those drugs were characterizedby relatively selective action on only one of the three main monoaminesystems thought to be involved in depression (i.e., 5-HT (serotonin),noradrenaline (norepinephrine), and dopamine). APP Textbook ofPsychopharmacology (A. F. Schatzberg and C. B. Nemeroff), AmericanPsychiatric Press, 2d. ed., (1998); Lexicon of Psychiatry, Nuerology andthe Neurosciences (F. J. Ayd, Jr.) Williams and Wilkins (1995). Theantidepressant efficacy of reboxetine is evidenced by its ability toprevent resperine-induced blepharospasm and hypothermia in mice, downregulation of β-adrenergic receptors and desensitization ofnoradrenaline-coupled adenylate cyclase. See M. Brunello and G. Racagni,“Rationale for the Development of Noradrenaline Reuptake Inhibitors,”Human Psychophramacology, vol. 13, S-13-519, Supp. 13-519 (1998).

[0009] According to a survey by Brian E. Leonard, desipramine,maprotiline, and lofepramine are relatively selective norepinephrinereuptake inhibitors with proven efficacy. These materials increase brainnoradrenaline and thereby function to relieve depression. Mianserin andmirtazepine also show antidepressant-like effects by increasingnoradrenaline availability by means of blocking the pre-synapticα₂-adrenoceptors. Still further, oxaprotiline, fezolamine, andtomoxetine are potent and selective norepinephrine reuptake inhibitorsthat lack neurotransmitter receptor interactions and, thus, do not causemany of the side effects characteristic of classical tricyclicantidepressants. See Brian E. Leonard, “The Role of Noradrenaline inDepression: A Review,” Journal of Psychopharmocology, vol. 11, no. 4(Suppl.), pp. S39-S47 (1997)

[0010] Reboxetine also is a selective norepinephrine reuptake inhibitor,which also produces fewer of the side effects associated with theadministration of classical tricyclic antidepressants. Theantidepressant efficacy of reboxetine is evidenced by its ability toprevent resperine-induced blepharospasm and hypothermia in mice, downregulation of β-adrenergic receptors and desensitization ofnoradrenaline-coupled adenylate cyclase. See M. Brunello and G. Racagni,“Rationale for the Development of Noradrenaline Reuptake Inhibitors.”Human Psychophramacology, vol. 13 (Supp.) 13-519 (1998).

[0011] Reboxetine generally is described in Melloni et al. U.S. Pat.Nos. 4,229,449, 5,068,433, and 5,391,735, and in GB 2,167,407, thedisclosures of which are hereby incorporated by reference. Chemically,reboxetine has two chiral centers and, therefore, exists as twoenantiomeric pairs of diastereomers, shown below as isomers (I) through(IV):

[0012] Many organic compounds exist in optically active forms, i.e.,they have the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound the prefixes R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes D and L, or (+) or (−), designate the sign ofrotation of plane-polarized light by the compound, with L or (−) meaningthat the compound is levorotatory. In contrast, a compound prefixed withD or (+) is dextrorotatory. There is no correlation between nomenclaturefor the absolute stereochemistry and for the rotation of an enantiomer.Thus, D-lactic acid is the same as (−)-lactic acid, and L-lactic acid isthe same as (+)-lactic acid. For a given chemical structure, each of apair of enantiomers are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomermay also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric, or racemic, mixture.

[0013] Stereochemical purity is important in the pharmaceutical field,where many of the most often prescribed drugs exhibit chirality. Forexample, the L-enantiomer of the beta-adrenergic blocking agent,propranolol, is known to be 100 times more potent than its D-enantiomer.Additionally, optical purity is important in the pharmaceutical drugfield because certain isomers have been found to impart a deleteriouseffect, rather than an advantageous or inert effect. For example, it isbelieved that the D-enantiomer of thalidomide is a safe and effectivesedative when prescribed for the control of morning sickness duringpregnancy, whereas its corresponding L-enantiomer is believed to be apotent teratogen.

[0014] When two chiral centers exist in one molecule, there are fourpossible stereoisomers: (R,R), (S,S), (R,S), and (S,R). Of these, (R,R)and (S,S) are an example of a pair of enantiomers (mirror images of eachother), which typically share chemical properties and melting pointsjust like any other enantiomeric pair. The mirror images of (R,R) and(S,S) are not, however, superimposable on (R,S) and (S,R). Thisrelationship is called diastereoisomeric, and the (S,S) molecule is adiastereoisomer of the (R,S) molecule, whereas the (R,R) molecule is adiastereoisomer of the (S,R) molecule.

[0015] Currently, reboxetine is commercially available only as a racemicmixture of enantiomers, (R,R) and (S,S) in a 1:1 ratio, and referenceherein to the generic name “reboxetine” refers to this enantiomeric, orracemic, mixture. Reboxetine is commercially sold under the trade namesof EDRONAX™, PROLIFT™, VESTRA™, and NOREBOX™. As previously noted,reboxetine has been shown to be useful in the treatment of humandepression. Orally administered reboxetine is readily absorbed andrequires once or twice a day administration. A preferred adult dailydose is in the range of about 8 to about 10 milligrams (mg). Theeffective daily dosage of reboxetine for a child is smaller, typicallyin a range of about 4 to about 5 mg. The optimum daily dosage for eachpatient, however, must be determined by a treating physician taking intoaccount the patient's size, other medications which the patient may betaking, identity and severity of the particular disorder, and all of theother circumstances of the patient.

[0016] Administration of reboxetine, however, can result in undesiredside effects associated with drug-drug interactions and in otherundesirable effects such as, for example, dizziness, insomnia,lightheadedness, changes in blood pressure, sweating, gastrointestinaldisturbances, sexual dysfunction in males, certain anticholinergic-likeeffects (e.g., tachyardia and urinary retention). It has been found thatsuch side effects occur, in part, because reboxetine lacks asufficiently high selectivity for inhibiting norepinephrine reuptake. Inother words, reboxetine is blocking reuptake of other monoamines, likeserotonin and dopamine, to a sufficient degree to contribute to theundesired side effects.

[0017] It has been reported that other antidepressants have a highpharmacological selectivity for inhibiting reuptake of norepinephrine.For example, oxaprotiline has a pharmacological selectivity with respectto inhibiting norepinephrine reuptake compared to serotonin reuptake ofabout 4166, based on a ratio of K_(i) values. The correspondingpharmacological selectivity for desipramine is about 377, and that formaprotiline is about 446. See Elliott Richelson and Michael Pfenning,“Blockade by Antidepressants and Related Compounds of Biogenic AmineUptake in Rat Brain Synaptosomes: Most Antidepressants Selectively BlockNorepinephrine Uptake,” European Journal of Pharmacology, vol. 14. pp.277-286 (1984). Despite the relatively high selectivity of oxaprotiline,desipramine, and maprotiline, these and other known materialsundesirably block receptor of other neurotransmitters to a sufficientdegree that they also contribute to adverse side effects.

[0018] Accordingly, there is a need in the art for a method of treatingindividuals suffering from a variety of conditions where inhibitingreuptake of norepinephrine provides a benefit, while reducing oreliminating the adverse side effects associated with conventionalnorepinephrine reuptake inhibitors. There also is a need for a methodthat selectively inhibits the reuptake of norepinephrine over otherneurotransmitters, like serotonin and dopamine. Specifically, there is aneed in the art for a highly selective (at one reuptake site), specific(with no activity at other receptors), and potent norepinephrinereuptake inhibitor. Furthermore, there is a need for pharmaceuticalcompositions containing a highly selective and potent norepinephrinereuptake inhibitor. Still further, there is a need for medicamentscontaining such pharmaceutical compositions, and the use of suchcompositions in the manufacture of such medicaments.

SUMMARY OF THE INVENTION

[0019] The present invention generally is directed to compositions andmethods of treating or preventing a variety of human conditions whereinhibition of norepinephrine reuptake provides a benefit and, morespecifically, where selective, specific, and potent inhibition ofnorepinephrine provides a benefit. More particularly, the presentinvention is directed to an effective treatment or prevention of suchconditions comprising administration of compounds, such as reboxetine oran optically pure (S,S) stereoisomer thereof, to a human.

[0020] Accordingly, one embodiment of the present invention is directedto a method of selectively inhibiting reuptake of norepinephrine, themethod comprising the step of administering a therapeutically effectiveamount of a composition to an individual, the composition comprising acompound having a pharmacological selectivity of serotonin(K_(i))/norepinephrine (K_(i)) of at least about 5000, preferably atleast about 10,000, and more preferably at least about 12,000.

[0021] Another embodiment of the present invention is directed to amethod of treating a human suffering from a condition, or preventingsaid condition, wherein inhibiting reuptake of norepinephrine provides abenefit, the method comprising the step of administering atherapeutically effective amount of a composition comprising a compoundhaving a pharmacological selectivity of serotonin (K_(i))/norepinephrine(K_(i)) of at least about 5000, preferably at least about 10,000, andmore preferably at least about 12,000.

[0022] Another embodiment of the present invention is directed to apreparation of a medicament from a composition comprising a compoundhaving a pharmacological selectivity of serotonin (K_(i))/norepinephrine(K_(i)) of at least about 5000, preferably at least about 10,000, andmore preferably at least about 12,000 to treat or prevent at least onenervous system disorder selected from the group consisting of addictivedisorders (including those due to alcohol, nicotine, and otherpsychoactive substances) and withdrawal syndrome, adjustment disorders(including depressed mood, anxiety, mixed anxiety and depressed mood,disturbance of conduct, and mixed disturbance of conduct and mood),age-associated learning and mental disorders (including Alzheimer'sdisease), anorexia nervosa, apathy, attention-deficit (or othercognitive) disorders due to general medical conditions,attention-deficit hyperactivity disorder (ADHD), bipolar disorder,bulimia nervosa, chronic fatigue syndrome, chronic or acute stress,chronic pain, conduct disorder, cyclothymic disorder, depression(including adolescent depression and minor depression), dysthymicdisorder, fibromyalgia and other somatoform disorders (includingsomatization disorder, conversion disorder, pain disorder,hypochondriasis, body dysmorphic disorder, undifferentiated somatoformdisorder, and somatoform NOS), generalized anxiety disorder (GAD),incontinence (i.e., stress incontinence, genuine stress incontinence,and mixed incontinence), inhalation disorders, intoxication disorders(alcohol addiction), mania, migraine headaches, obesity (i.e., reducingthe weight of obese or overweight patients), obsessive compulsivedisorders and related spectrum disorders, oppositional defiant disorder,panic disorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder (i.e., premenstrual syndrome and lateluteal phase dysphoric disorder), psychotic disorders (includingschizophrenia, schizoaffective and schizophreniform disorders), seasonalaffective disorder, sleep disorders (such as narcolepsy and enuresis),social phobia (including social anxiety disorder), specificdevelopmental disorders, selective serotonin reuptake inhibition (SSRI)“poop out” syndrome (i.e., wherein a patient who fails to maintain asatisfactory response to SSRI therapy after an initial period ofsatisfactory response), and TIC disorders (e.g., Tourette's Disease).

[0023] Another embodiment of the present invention is directed to use ofa composition comprising a compound having a pharmacological selectivityof serotonin (K_(i))/norepinephrine (K_(i)) of at least about 5000,preferably at least about 10,000, and more preferably at least about12,000, in a manufacture of a medicament to treat or prevent at leastone of the aforementioned nervous system disorders.

[0024] An example of a compound having a pharmacological selectivity ofserotonin (K_(i))/norepinephrine (K_(i)) of at least about 5000, isoptically pure (S,S) reboxetine substantially free of its (R,R)stereoisomer. Individuals treated with optically pure (S,S) reboxetinedo not experience certain adverse side effects associated with theadministration of the racemic mixture of (R,R) and (S,S) reboxetine. Thepresent invention therefore includes administering optically pure (S,S)reboxetine to a human to selectively inhibit norepinephrine reuptake,and thereby control, reduce, or eliminate adverse effects caused by theadministration of the racemic mixture of reboxetine.

[0025] More specifically, another embodiment of the present invention isdirected to a method of treating or preventing a human condition whereininhibiting reuptake of norepinephrine provides a benefit. The methodcomprises the step of administering a therapeutic amount, typicallyabout 0.5 to about 10 mg/day, of optically pure (S,S) reboxetine, or apharmaceutically acceptable salt thereof. Optically pure (S,S)reboxetine is substantially free of (R,R) reboxetine.

[0026] Optically pure (S,S) reboxetine is advantageous over prior,treatment or prevention methods which utilized a racemic mixture of(R,R) and (S,S) reboxetine. In particular, it has been found thattreatments using compositions containing an optically pure (S,S)reboxetine are about 5 to about 8.5 times more effective at inhibitingthe reuptake of norepinephrine than compositions containing the racemicmixture of the (R,R) and (S,S) stereoisomers. Therefore, reuptakeblockage can be achieved with much lower dosages. Accordingly, thepresent invention may permit a substantial reduction in the customarydaily dosage of the racemic mixture (i e., the commercially availablereboxetine) by about 50% to about 80% because of the use of an opticallypure (S,S) reboxetine. In addition, treatments utilizing the opticallypure (S,S) reboxetine may result in fewer undesirable adverse sideeffects associated with the treatment because of the high selectivityand potency of (S,S) reboxetine with respect to inhibiting the reuptakeof norepinephrine.

[0027] Another embodiment of the present invention is directed to amethod of treating or preventing a nervous system disorder comprisingthe step of administering a therapeutically effective dose of racemicreboxetine to an individual, wherein the disorder is at least one of anadjustment disorder, an age-associated learning and mental disorder,anorexia nervosa, apathy, an attention-deficit disorder due to generalmedical conditions, bipolar disorder, bulimia nervosa, chronic fatiguesyndrome, chronic or acute stress, chronic pain, cyclothymic disorder,dysthymic disorder, fibromyalgia and other somatoform disorders,incontinence, mania, migraine headaches, obesity, peripheral neuropathy,post-traumatic stress disorder, premenstrual dysphoric disorder, apsychotic disorder, seasonal affective disorder, a sleep disorders, aspecific developmental disorders, SSRI “poop out” syndrome, and TICdisorders. Other embodiments of the present invention are directed to apreparation of a medicament from a composition comprising reboxetine anda use of reboxetine in a manufacture of the medicament to treat orprevent at least one of the aforementioned nervous system disorders.

[0028] Additional benefits and features of the present invention willbecome apparent to those skilled in the art from a review of thefollowing detailed description, taken in conjunction with the exampleand the appended claims. It should be noted, however, that while theinvention is susceptible of embodiments in various forms, describedhereafter are specific preferred embodiments of the invention with theunderstanding that the present disclosure is intended as illustrative,and is not intended to limit the invention to the specific embodimentsdescribed herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Reboxetine is a known compound that is active on the centralnervous system, and has been used as an antidepressant. Heretofore, useof reboxetine has been limited to the treatment of depression,oppositional defiant disorder, attention-deficit/hyperactivity disorder,and conduct disorder. These proposed treatments are disclosed inInternational Publication Nos. WO 99/15163, WO 95/15176, and WO99/15177. These treatment methods are limited to administration of aracemic mixture of the (S,S) and (R,R) reboxetine stereoisomers.

[0030] Reboxetine does not act like most antidepressants. Unliketricyclic antidepressants, and even selective serotonin reuptakeinhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAThypothermia test, indicating that reboxetine is not a SSRI. Brian E.Leonard, “Noradrenaline in basic models of depression.”European-Neuropsychopharmacol, 7 Suppl. 1 pp. S11-6 and S71-3 (April1997). Reboxetine is a selective norepinephrine reuptake inhibitor, withonly marginal serotonin and no dopamine reuptake inhibitory activity.Reboxetine displays no anticholinergic binding activity in differentanimal models, and is substantially devoid of monoamine oxidase (MAO)inhibitory activity. Racemic reboxetine exhibits a pharmacologicalselectivity of serotonin (K_(i))/norepinephrine (K_(i)) of about 80. TheK_(i) values are discussed in more detail hereafter.

[0031] Another embodiment of the present invention includes a method ofselectively inhibiting reuptake of norepinephrine, the method comprisingthe step of administering a therapeutically effective amount of acomposition to an individual, the composition comprising a compoundhaving a pharmacological selectivity of serotonin (K_(i))/norepinephrine(K_(i)) of at least about 5000, preferably at least about 10,000, andmore preferably at least about 12,000.

[0032] Another embodiment of the present invention is directed to acomposition comprising a compound having a pharmacological selectivityof serotonin (K_(i))/norepinephrine (K_(i)) of at least about 5000,preferably at least about 10,000, and more preferably at least about12,000. The inventive composition is useful in the treatment orprevention of diseases, disorders, and conditions (described in moredetail below) wherein inhibition of reuptake of norepinephrine isbeneficial. An example of such a compound is an optically pure (S,S)stereoisomer of reboxetine, or a pharmaceutically effective saltthereof.

[0033] To determine the degree of selectivity of a compound to bind tothe norepinephrine reuptake site, the inhibition constant (or K_(i)value) of the compound for serotonin reuptake site was divided by theK_(i) value for norepinephrine reuptake site. A lower value of K_(i) fornorepinephrine reuptake indicates greater binding affinity tonorepinephrine receptors. A higher serotonin (K_(i))/norepinephrine(K_(i)) ratio indicates a greater selectivity for binding thenorepinephrine receptor. Accordingly, the present invention is directedto a composition comprising a compound having a pharmacologicalselectivity of serotonin (K_(i))/norepinephrine (K_(i)) of at leastabout 5000, preferably at least about 10,000, and more preferably atleast about 12,000, as noted above. Furthermore, it is envisioned thatselectivity values far in excess of 12,000, such as 25,000, 50,000,75,000, and even up to 100,000 or greater, also are beneficial.

[0034] The compositions of the present invention, when employed ineffective amounts in accordance with the present invention, areselective with respect to the norepinephrine reuptake site, but do notcause significant blockade of receptors associated with undesirable sideeffects e.g., serotonin and dopamine receptors. In other words, a doseof the inventive composition capable of inhibiting the reuptake ofnorepinephrine, is essentially ineffective in eliciting blockade ofother neurotransmitter receptors. Inhibition constants (K_(i) values),typically reported in units of nanamolars (nM), were calculated from theIC₅₀ values according to the method set forth in Y. C. Cheng and W. H.Prusoff, “Relationship Between the Inhibitory Constant (K_(i)) and theConcentration of Inhibitor Which Causes 50% Inhibition (IC₅₀) of anEnzymatic Reaction,” Biochemical Pharmacology, vol. 22, pp. 3099-3108(1973).

[0035] Another embodiment of the present invention is directed to aneffective method using an optically pure (S,S) stereoisomer ofreboxetine to treat or prevent conditions wherein inhibition of reuptakeof norepinephrine is beneficial. (S,S) Reboxetine is an effective,selective inhibitor of norepinephrine reuptake and, accordingly, doselevels can be substantially reduced in comparison to racemic reboxetine.In addition, individuals treated with an optically pure (S,S) reboxetinedo not experience certain adverse effects associated with theadministration of the racemic mixture of (R,R) and (S,S) reboxetine.Accordingly, another embodiment of the present invention includesadministering a therapeutic amount of an optically pure (S,S) reboxetineto a human to inhibit the reuptake of norepinephrine, and to control,reduce, or eliminate adverse effects associated with administration ofracemic reboxetine.

[0036] Yet another embodiment of the present invention is directed to amethod of treating or preventing a human condition wherein inhibitingreuptake of norepinephrine provides a benefit. The method comprises thestep of administering, and preferably orally administering, a total doseof about 0.1 mg/day to about 10 mg/day, more preferably about 0.5 toabout 10 mg day of an optically pure (S,S) reboxetine, or apharmaceutically acceptable salt thereof, to an individual.

[0037] As used herein, the term “reboxetine” refers to the racemicmixture of the (R,R) and (S,S) enantiomers of reboxetine. In contrast,the term “(S,S) reboxetine” refers to only the (S,S) stereoisomer.Similarly, the term “(R,R) reboxetine” refers to only the (R,R)stereoisomer.

[0038] The phrases “optically pure (S,S) reboxetine” and “substantiallyfree of its (R,R) stereoisomer,” as used herein, mean that thecomposition contains a greater proportion of (S,S) reboxetine inrelation to (R,R) reboxetine. In a preferred embodiment, the phrasesmean that the composition is at least 90 percent by weight (wt. %) of(S,S) reboxetine, and 10 wt. % or less of (R,R) reboxetine. In a morepreferred embodiment the phrases mean that the composition contains atleast 97 wt. % of (S,S) reboxetine, and 3 wt. % or less of (R,R)reboxetine. In an even more preferred embodiment, the phrases mean thatthe composition contains at least 99 wt. % of (S,S) reboxetine, and 1wt. % or less of (R,R) reboxetine. In a most preferred embodiment, thephrases “optically pure (S,S) reboxetine” and “substantially free of its(R,R) stereoisomer,” as used herein, mean that the composition containsgreater than 99 wt. % of (S,S) reboxetine. The foregoing percentages arebased upon the total amount of reboxetine present in the composition.The phrases “substantially free of (R,R) reboxetine,” “substantiallyoptically pure (S,S) stereoisomer of reboxetine,” “substantiallyoptically pure (S,S) reboxetine,” “optically pure (S,S) stereoisomer ofreboxetine,” and “optically pure (S,S) reboxetine” are also encompassedby the above-described amounts.

[0039] The phrases “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to salts prepared frompharmaceutically acceptable acids or bases, including organic andinorganic acids and bases. Because the active compound (i.e., (S,S)reboxetine) used in the present invention is basic, salts may beprepared from pharmaceutically acceptable acids. Suitablepharmaceutically acceptable acids include acetic, benzenesulfonic(besylate), benzoic, p-bromophenylsulfonic, camphorsulfonic, carbonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, hydroiodic, isethionic, lactic, maleic, malic, mandelic,methanesulfonic (mesylate), mucic, nitric, oxalic, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and thelike. Examples of such pharmaceutically acceptable salts of (S,S)reboxetine, thus, include, but are not limited to, acetate, benzoate,β-hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1,4-dioate,carpoate, chloride, chlorobenzoate, citrate, dihydrogenphosphate,dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-1,6-dioate,hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate,metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate,monohydrogenphosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,oxalate, phenylbutyrate, phenylproionate, phosphate, phthalate,phylacetate, propanesulfonate, propiolate, propionate, pyrophosphate,pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, sulfonate,tartrate, xylenesulfonate, and the like. A preferred pharmaceutical saltof (S,S) reboxetine is methanesulfonate (i.e., mesylate), which isprepared using methanesulfonic acid.

[0040] The phrases “side effects,” “adverse effects,” and “adverse sideeffects” in relation to reboxetine include, but are not limited to,dizziness, insomnia, lightheadedness, changes in blood pressure,gastrointestinal disturbances, sexual dysfunction in males,extrapyramidal side effects, certain anticholinergic-like effects (e.g.,tachycardia, blurred vision), and undesired side effects associated withwith drug-drug interactions.

[0041] As used herein, the terms “treat,” “treatment,” and “treating,”refer to: (a) preventing a disease, disorder, or condition fromoccurring in a human which may be predisposed to the disease, disorderand/or condition but has not yet been diagnosed as having it: (b)inhibiting the disease, disorder, or condition, i.e., arresting itsdevelopment, and (c) relieving the disease, disorder, or condition,i.e., causing regression of the disease, disorder and or condition. Inother words, the terms “treat,” “treatment,” and “treating,” extend toprophylaxis, in other words “prevent,” “prevention,” and “preventing,”as well as treatment of established conditions. Accordingly, use of theterms “prevent,” “prevention,” and “preventing,” would be anadministration of the pharmaceutical composition to a person who has inthe past suffered from the aforementioned conditions, such as, forexample, migraine headaches, but is not suffering from the conditions atthe moment of the composition's administration. For the sake ofsimplicity, the term “conditions” as used hereinafter encompassesconditions, diseases, and disorders.

[0042] Methods and compositions of the present invention are useful intreating a human condition wherein inhibiting reuptake of norepinephrineprovides a benefit. The method comprises the step of administering, andpreferably orally administering, a sufficient amount of the inventivecomposition to provide a total dose of about 0.1 to about 10 mg/day ofthe selective compound to an individual.

[0043] More specifically, administration of the inventive composition(e.g., a composition containing an optically pure (S,S) reboxetine) iseffective in treating various human conditions including, but notlimited to, addictive disorders (including those due to alcohol,nicotine, and other psychoactive substances) and withdrawal syndrome,adjustment disorders (including depressed mood, anxiety, mixed anxietyand depressed mood, disturbance of conduct, and mixed disturbance ofconduct and mood), age-associated learning and mental disorders(including Alzheimer's disease), anorexia nervosa, apathy,attention-deficit (or other cognitive) disorders due to general medicalconditions, attention-deficit hyperactivity disorder (ADHD), bipolardisorder, bulimia nervosa, chronic fatigue syndrome, chronic or acutestress, chronic pain, conduct disorder, cyclothymic disorder, depression(including adolescent depression and minor depression), dysthymicdisorder, fibromyalgia and other somatoform disorders (includingsomatization disorder, conversion disorder, pain disorder,hypochondriasis, body dysmorphic disorder, undifferentiated somatoformdisorder, and somatoform NOS), generalized anxiety disorder (GAD),incontinence (i.e., stress incontinence, genuine stress incontinence,and mixed incontinence), inhalation disorders, intoxication disorders(alcohol addiction), mania, migraine headaches, obesity (i.e., reducingthe weight of obese or overweight patients), obsessive compulsivedisorders and related spectrum disorders, oppositional defiant disorder,panic disorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder (i.e., premenstrual syndrome and lateluteal phase dysphoric disorder), psychotic disorders (includingschizophrenia, schizoaffective and schizophreniform disorders), seasonalaffective disorder, sleep disorders (such as narcolepsy and enuresis),social phobia (including social anxiety disorder), specificdevelopmental disorders, selective serotonin reuptake inhibition (SSRI)“poop out” syndrome (i.e., wherein a patient who fails to maintain asatisfactory response to SSRI therapy after an initial period ofsatisfactory response), and TIC disorders (e.g., Tourette's Disease).

[0044] The administration of the inventive composition is very effectivein the treatment of addictive disorders and withdrawal syndromes,adjustment disorders, apathy, attention-deficit hyperactivity disorder,attention-deficit disorders due to medical conditions, bulimia nervosa,chronic fatigue syndrome, chronic or acute stress, depression, dysthymicdisorder, generalized anxiety disorder (GAD), nicotine addiction, panicdisorder, post-traumatic stress disorder, premenstrual dysphoricdisorder, schizoaffective disorder, and SSRI “poop out” syndrome.Furthermore, the administration of (S,S) reboxetine is especiallyeffective in treatment or prevention of addictive disorders andwithdrawal syndromes, apathy, attention-deficit hyperactivity disorder,attention-deficit disorders due to medical conditions, chronic fatiguesyndrome, chronic or acute stress, dysthymic disorder, depression,nicotine addiction, obesity, post-traumatic stress disorder, and SSRI“poop out” syndrome.

[0045] Reference to treatments for “nicotine addiction” herein alsoincludes treatments for smoking cessation. Many of the foregoing humanconditions are generally described by the American PsychiatricAssociation in their publication entitled. “Diagnostic and StatisticalManual of Mental Disorders,” 4th ed. rev. (Washington D.C. 1994), thedisclosure of which is hereby incorporated by reference. Generaldescriptions of addictive disorders, including disorders related tointoxication and inhalants and, and nicotine addiction may be found inmany standard references, such as R. E. Hales et al., “The AmericanPsychiatric Press Textbook of Psychiatry,” 3d. ed. (1999), thedisclosure of which is hereby incorporated by reference.

[0046] An inventive composition also can be used to treat migraineheadaches. Furthermore, the inventive composition can be used to treatheadaches in migraineurs or people suffering from migraine headaches,including the treatment of symptoms of an existing headache, treatmentto prevent the occurrence, intensity, and duration of a headache,prophylactic use to prevent or reduce the incidence or duration ofmigraines, as an adjuvant to facilitate the effectiveness of an abortivemedication or co-administered with other medications (including abortivemedications) to reduce the required dosages (and side effects) of thosemedications.

[0047] A preferred embodiment of the inventive composition includes(S,S) reboxetine. It is known that commercially-available reboxetine isa racemic mixture of the (R,R) and (S,S) enantiomers of2-[(2-ethoxyphenoxy)(phenyl)methyl]morpholine. It has now beendiscovered that the (S,S) stereoisomer is the most active and the mostselective stereoisomer with respect to inhibiting the reuptake ofnorepinephrine. In addition, when administered to an individual, in thedosages described herein, as awn optically pure material (i.e., in thesubstantial absence of its (R,R) diastereomer), the individual does notexperience many of the adverse side effects associated with theadministration of commercially-available reboxetine. Furthermore, it hasfurther been discovered that the (S,S) and (R,R) enantiomers have areversed selectivity for the norepinephrine neurotransmitter in relationto the serotonin neurotransmitter, and an optically pure (S,S)reboxetine is significantly more effective at inhibiting reuptake ofnorepinephrine than either the (R,R) enantiomer or a racemic mixture ofthe (S,S) and (R,R) enantiomers.

[0048] Specifically, it has been found that compositions containing anoptically pure (S,S) reboxetine are about 5 to about 8.5 times moreeffective at inhibiting the reuptake of norepinephrine than compositionscontaining the racemic mixture of the (R,R) and (S,S) stereoisomers.Accordingly, the typical daily dosage of the racemic mixture (i.e.,commercially availabe reboxetine) can be reduced by about 50% to about80% when using an optically pure (S,S) reboxetine. The reduction indosage does not lead to a reduction in efficacy, but the reduction orelimination of various adverse side effects was observed.

[0049] In particular, because an optically pure (S,S) reboxetineselectively inhibits norepinephrine reuptake compared to serotoninreuptake, adverse side effects associated with serotonin reuptake arereduced or eliminated. Such adverse side effects include, but are notlimited to, gastrointestinal disturbances, anxiety, sexual dysfunction,and undesirable side effects associated with drug-drug interactions.

[0050] The synthesis of a racemic mixture of reboxetine is disclosed inMelloni et al. U.S. Pat. No. 4,229,449. Individual stereoisomers ofreboxetine can be obtained by resolution of the racemic mixture ofenantiomers using conventional methods generally known by those skilledin the art. Such methods include, but are not limited to, resolution bysimple crystallization and chromatographic techniques, for example, asset forth in GB 2,167,407.

[0051] While it is possible to administer a highly selectivenorepinephrine reuptake inhibitor directly without any formulation, acomposition preferably is administered in the form of pharmaceuticalmedicaments comprising the selective norepinephrine reuptake inhibitor.The inventive composition can be administered in oral unit dosage formssuch as, tablets, capsules, pills, powders, or granules. The inventivecomposition also can be introduced parenterally, (e.g., subcutaneously,intravenously, or intramuscularly), using forms known in thepharmaceutical art. The inventive composition further can beadministered rectally or vaginally in such forms as suppositories orbougies. The inventive composition also can be administered topically ortransdermally, such as with a “patch” containing active ingredient.Transdermal delivery patches can be used to provide continuous,pulsatile, or on-demand infusion of the inventive compositions incontrolled amounts. The construction and use of transdermal deliverypatches are well known in the pharmaceutical art, and are described, forexample, in U.S. Pat. Nos. 3,742,951, 3,742,951, 3,797,494, 3,996,934,4,031,894, and 5,023,252.

[0052] It may be desirable or necessary to introduce the inventivecomposition or pharmaceutical compositions containing the selectivenorepinephrine reuptake inhibitor to the brain, either directly orindirectly. Direct techniques usually involve placement of a suitabledrug delivery catheter into the ventricular system to bypass theblood-brain barrier. One such suitable delivery system used for thetransport of biological factors to specific anatomical regions of thebody is described in U.S. Pat. No. 5,011,472, the disclosure of which isincorporated herein by reference.

[0053] In general, the preferred route of administering the inventivecomposition is oral, with a once or twice a day administration. Thedosage regimen and amount for treating patients with the inventivecomposition is selected in accordance with a variety of factorsincluding, for example, the type, age, weight, sex, and medicalcondition of the patient, the severity of the condition, the route ofadministration and the particular compound employed, either racemate orpure enantiomer. An ordinarily skilled physician or psychiatrist canreadily determine and prescribe an effective (i.e., therapeutic) amountof the compound to prevent or arrest the progress of the condition. Inso proceeding, the physician or psychiatrist could employ relatively lowdosages at first, subsequently increasing the dose until a maximumresponse is obtained.

[0054] Pharmaceutical compositions suitable for oral administration canbe of any convenient form, such as sachets, tablets, capsules, pills, oraerosol sprays, each containing a predetermined amount of the activecompound either as a powder or granules, or as a solution or asuspension in an aqueous liquid, a non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such compositions can beprepared by any method that includes the step of bringing the activecompound either into intimate association with a carrier, whichconstitutes one or more necessary or desirable ingredients. Generally,the compositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into a desiredform.

[0055] For example, a tablet can be prepared by compression or moldingtechniques, optionally, using one or more accessory ingredients.Compressed tablets can be prepared by compressing the active ingredientin a suitable machine into a free-flowing form, such as a powder orgranules. Thereafter, the compressed, free-flowing form optionally canbe mixed with a binders, diluents, lubricants, disintegrating agents,effervescing agents, dyestuffs, sweeteners, wetting agents, andnon-toxic and pharmacologically inactive substances typically present inpharmaceutical compositions. Molded tablets can be made by molding amixture of the powdered compound moistened with an inert liquid diluentin a suitable machine.

[0056] Suitable binders for use in the pharmaceutical preparationinclude, for example, starches, gelatine, methylcellulose, gum arabic,tragacanth, and polyvinylpyrrolidone. Suitable diluents for use in thepharmaceutical preparation include, for example, lactose, dextrose,sucrose, mannitol, sorbitol, and cellulose. Suitable lubricants for usein the pharmaceutical preparation include, for example, silica, talc,stearic acid, magnesium or calcium stearate, and or polyethyleneglycols. Suitable disintegrating agents for use in the pharmaceuticalpreparation include, for example, starches, alginic acid, and alginates.Suitable wetting agents for use in the pharmaceutical preparationinclude, for example, lecithin, polysorbates, and laurylsulfates.Generally, any effervescing agents, dyestuffs, and/or sweetenersknown-by those of ordinary skill in the art can be used in thepreparation of a pharmaceutical composition.

[0057] Desirably, daily dose of the composition (e.g., tablet, sachet,or capsule) contains from about 0.1 to about 10 mg of optically pure(S,S) reboxetine, and is substantially free of its (R,R) stereoisomer.More preferably, each dose of the composite contains about 0.5 to about8 mg of the active ingredient, optically-pure (S,S) reboxetine, and issubstantially free of its (R,R) stereoisomer. Even more preferably,however, each dose contains from about 0.5 to about 5 mg of the activeingredient, such as an optically-pure (S,S) reboxetine, and issubstantially free of its (R,R) stereoisomer. This dosage form permitsthe full daily dosage of about 0.5 to about 2.5 mg to be administered inone or two oral doses. This will allow for tablets containing 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 mg of optically pure(S,S) reboxetine.

[0058] In another embodiment, a preferred daily dose of the composition(e.g., tablet, sachet, or capsule) contains from about 0.1 to about 0.9mg of optically pure (S,S) reboxetine, and is substantially free of its(R,R) stereoisomer. More preferably, each dose of the compositioncontains about 0.5 to about 0.8 mg of the active ingredient,optically-pure (S,S) reboxetine, and is substantially free of its (R,R)stereoisomer. Even more preferably, however, each dose contains fromabout 0.5 to about 0.75 mg of the active ingredient, optically pure(S,S) reboxetine, and is substantially free of its (R,R) stereoisomer.This dosage form permits the full daily dosage of about 0.5 to about 0.9mg to be administered in one oral dose.

[0059] Patients suffering from depression, nicotine addiction, conductdisorder, oppositional defiant disorder, and/or attention-deficithyperactivity disorder will benefit from the administration of theinventive composition, and specifically one containing an optically pure(S,S) reboxetine, regardless of these or other co-morbid conditions.Diagnostic criteria for these disorders generally are provided by theAmerican Psychiatric Association and published in their “Diagnostic andStatistical Manual of Mental Disorders.” 4th ed. rev. (Washington D.C.1994), and in International Publication Nos. WO 99/15177, WO 99/15176,and WO 99/15163, the disclosures of which are hereby incorporated byreference.

[0060] Furthermore, patients suffering from addictive disorders andwithdrawal syndromes, adjustment disorders, apathy, attention-deficithyperactivity disorder, attention-deficit disorders due to medicalconditions, bulimia nervosa, chronic fatigue syndrome, chronic or acutestress, depression, dysthymic disorder, generalized anxiety disorder(GAD), nicotine addiction, panic disorder, post-traumatic stressdisorder, premenstrual dysphoric disorder, schizoaffective disorder, andSSRI “poop out” syndrome will benefit from the administration of theinventive composition, and specifically one containing optically pure(S,S) reboxetine.

[0061] These disorders display similar patterns in children,adolescents, and adults. Hence, methods of the present invention areeffective in the treatment of child, adolescent, and adult patients. Forpurposes of the present invention, a child is considered to be a personbelow the age of puberty, an adolescent is considered to be a personbetween the age of puberty and up to about 18 years of age, and an adultgenerally is a person of at least about 18 years of age. As previouslynoted, the optimum daily dosage for each patient must be determined by atreating physician taking into account each patient's size, othermedications which the patient is taking, identity and severity of thedisorder, and all of the other circumstances of the patient.

[0062] As stated above, reboxetine acts as an antidepressant.Reboxetine, however, does not act like most antidepressants. Unliketrycyclic antidepressants, and even selective serotonin reuptakeinhibitors (SSRIs). reboxetine is ineffective in the 8-OH-DPAThypothermia test, indicating that reboxetine is not a selectiveserotonin reuptake inhibitor. Rather, reboxetine is selective for thenoradrenergic system. Reboxetine is not an SSRI, but is a novel,selective, noradrenaline reuptake inhibitor (NRI). B. Leonard,“Noradrenaline in basic models of depression.”European-Neuropsychopharmacol, 7 Suppl. 1 pp. S11-6 and S71-3 (April,1997). Unlike most prior generation drugs, reboxetine is a highlyselective norepinephrine reuptake inhibitor, with only marginalserotonin and no dopamine reuptake inhibitory activity. Reboxetinedisplays no anticholinergic binding activity in different animal models,and is devoid of monoamine oxidase (MAO) inhibitory activity.

[0063] Reboxetine also is a highly potent, pharmacologically specific,and fast acting agent. Investigations indicate that reboxetine haspotent antireserpine activity, and combines the inhibitory properties ofclassical tricyclic antidepressants on the reuptake of noradrenalinewith an ability to desensitize β-adrenergic receptor function, withoutshowing any appreciable blocking action at muscarinic, cholinergic,histaminergic, and α-adrenergic receptors. Moreover, reboxetine showsless vagolytic activity than tricyclic antidepressants, and no evidenceof cardiotoxicity.

[0064] Accordingly, in another embodiment of the invention, racemicreboxetine can be used to treat or prevent a number of mental andneurological disorders. Specifically, reboxetine has been foundparticularly useful for treating or enhancing the treatment orprevention of a variety of psychiatric symptoms or disorders, withgreater efficacy and with fewer side effects than with treatment byknown drugs. Furthermore, reboxetine may also be used to treat, or toenhance the treatment or prevention of, other specific psychiatricsymptoms or disorders.

[0065] Mental and neurological disorders that may be treated orprevented by administration of a therapeutically effective amount of aracemic reboxetine (or a derivative or pharmaceutically acceptable saltsthereof) include, but are not limited to adjustment disorders (includingdepressed mood, anxiety, mixed anxiety and depressed mood, disturbanceof conduct, and mixed disturbance of conduct and mood), age-associatedlearning and mental disorders (including Alzheimer's disease), anorexianervosa, apathy, attention-deficit (or other cognitive) disorders due togeneral medical conditions, bipolar disorder, bulimia nervosa, chronicfatigue syndrome, chronic or acute stress, chronic pain, cyclothymicdisorder, dysthymic disorder, fibromyalgia and other somatoformdisorders (including somatization disorder, conversion disorder, paindisorder, hypochondriasis, body dysmorphic disorder, undifferentiatedsomatoform disorder, and somatoform NOS), incontinence (i.e., stressincontinence, genuine stress incontinence, and mixed incontinence),mania, migraine headaches, obesity (i.e., reducing the weight of obeseor overweight patients), peripheral neuropathy, post-traumatic stressdisorder, premenstrual dysphoric disorder (i.e., premenstrual syndromeand late luteal phase dysphoric disorder), psychotic disorders(including schizophrenia, schizoaffective and schizophreniformdisorders), seasonal affective disorder, sleep disorders (such asnarcolepsy and enuresis), specific developmental disorders, selectiveserotonin reuptake inhibition (SSRI) “poop out” syndrome, and TICdisorders (e.g., Tourette's Disease).

[0066] Similar to (S,S) reboxetine, racemic reboxetine also can be usedto treat humans suffering from migraine headaches, paticularly to reducethe frequency, duration, intensity, and or complications resulting frommigraine headaches. Furthermore, racemic reboxetine can be used toprevent migraine headaches.

[0067] Additionally, racemic reboxetine can be used to treatincontinence (i.e., stress incontinence, genuine stress incontinence,and mixed incontinence). Stress urinary incontinence is a symptomdescribing involuntary loss of urine on carrying out any activity thatraises intra-abdominal pressure such as coughing or sneezing. Stressincontinence is also a clinical sign, that is the observation by a caregiver of a jet of urine escaping from the urethral meatus (opening) whenthe patient coughs or strains. Genuine Stress Incontinence is thepathological diagnosis of an incompetent urethral sphincter as diagnosedby Urodynamic testing. Mixed incontinence is stress incontinence incombination with urge incontinence. The latter is a part of the symptomcomplex of the Overative Bladder. Retention may be due to outflowobstruction (e.g., high urethral pressure), poor detrusor (bladdermuscle) contractility or lack of coordination between detrusorcontraction and urethral relaxation.

[0068] The racemate form of reboxetine is well tolerated and has a widesafety range. Racemic reboxetine can be administered to an individual inan amount in a range of about 2 to about 20 milligrams per patient perday (mg/day), and preferably about 4 to about 10 mg/day, and morepreferably about 6 to about 10 mg/day. Depending upon the formulationand the individual's disorder, the total daily dosage can beadministered in small amounts up to two times a day. Reboxetinetypically is administered orally, for example, in the form of tablets,but can be adminstered parentally, transdermally, rectally, orvaginally.

[0069] A preferred method of administering racemic reboxetine is oraldosing once or twice a day. It can also be administered at dosages ofabout 2, 4, 6, 8, 10, or 12 mg/day or fractions thereof. For example,suitable administrations could be about 4 mg in the morning and about 2or about 4 mg in the afternoon or evening. In some patients, the idealdosing would be about 3 to about 5 mg in the morning and about 3 toabout 5 mg in the afternoon. A skilled physician or psychiatrist candetermine the precise level of dosing. The ideal dosing is routinelydetermined by an evaluation of clinical trials and the needs of specificpatients.

[0070] In accordance with the present invention, the racemic reboxetinealso can be administered as the free base or a pharmaceuticallyacceptable salt thereof. The phrases “pharmaceutically acceptable salts”or “a pharmaceutically acceptable salt thereof” refer to salts preparedfrom pharmaceutically acceptable acids or bases, including organic andinorganic acids and bases as described above with respect to the saltsof optically pure (S,S) reboxetine. A preferred pharmaceutical salt ofreboxetine is methanesulfonate (i.e., mesylate), which is prepared usingmethanesulfonic acid.

[0071] Treatment or prevention of above disorders involves theadministration of reboxetine in a manner and form that result in areduction in the symptoms of the disease or disorder. Typically, thesymptoms exhibited by children, adolescents, and adults are similar toeach other. Hence, as noted above, methods of the present invention areeffective in the treatment of child, adolescent, and adult patients.

EXAMPLE

[0072] This example demonstrates the superior pharmacologicalselectivity and potency of a composition according to the presentinvention. More specifically, this example demonstrates the superiorpharmacological selectivity and potency of (S,S) reboxetine compared toits (R,R) stereoisomer and to racemic reboxetine.

[0073] Sprague-Dawley rats weighing about 250 to about 300 grams (g)were decapitated, and cerebral cortical tissue was removed immediately.Cerebral cortices were homogenized in nine volumes of medium eachcontaining 0.32 molar (M) sucrose using a rotating pestle. The obtainedhomogenate was centrifuged at about 1000×g for about 10 minutes at about4° C. A supernatant was collected and further centrifuged at about20,000×g, for about 20 minutes at a temperature of about 4° C. A proteinpellet resulting from the centrifuge steps was re-suspended in aKreb's-Hepes buffer to result in a protein concentration of about 2mg/ml of buffer. The buffer was maintained at a pH of about 7.0 andcontained: 20 mM Hepes; 4.16 mM NaHCO₃; 0.44 mM KH₂PO₄; 0.63 mM NaH₂PO₄;127 mM NaCl; 5.36 mM KCl; 1.26 mM CaCl₂; and 0.98 mM MgCl₂.

[0074] Protein/buffer suspension was introduced into 166 assay tubessuch that about 30 μg (10⁻⁶ grams) to about 150 μg of the protein wasadded to each of 166 assay tubes (i.e., 80 assays per transporterassay). Binding to serotonin and norepinephrine reuptake sites wasdetermined as follows. Synaptosomal uptake of ³H-norpinephrine wasdetermined as follows. About 1.4 nanomolar of [³H]citalopram and about1.9 nM of [³H]nisoxetine were used to label serotonin and norepinephrinereuptake sites, respectively. Nonspecific binding was defined by 100micromolar (μM) fluoxetine (for serotonin) and 10 μM desipramine (fornorepinephrine). Incubation in total assay volume of about 500microliters (μl) was carried out for about 60 minutes (for serotonin)and 120 minutes (for norepinephrine). Both incubations were carried outat about 25° C., and terminated by rapid filtration through a 48-wellcell harvester though GFB filters (pre-soaked with about 0.5 PEI forabout 4 hours) in a 3×5 ml of ice-cold 200 mM tris-HCl, pH 7.0.Punched-out filters were placed into 7 ml minivials and radioactiveassayed by liquid scintillation counting.

[0075] The ability of reboxetine (i.e., racemic mixture of (R,R) and(S,S) reboxetine), (R,R) reboxetine, and (S,S) reboxetine to bind tonorepinephrine and serotonin reuptake sites was evaluated in bindingassays using the two radioligands, [³H]citalopram and [³H]nisoxetine.The concentration of the test compound required to inhibit 50% of thespecific binding at the two reuptake sites (IC₅₀ values) were determinedby non-linear least square regression analysis. A conversion of IC₅₀values to K_(i) values was performed using the Cheng-Prusoff equationpresented below:

K _(i) =IC ₅₀/(1−([L]/[K _(d) of L])),

[0076] wherein [L] is the radioligand concentration used in nM, andK_(d) is the binding affinity of L in nM. See Y. C. Cheng and W. H.Prusoff. “Relationship Between the Inhibitory Constant (K_(i)) and theConcentration of Inhibitor Which Causes 50% Inhibition (IC₅₀) of anEnzymatic Reaction,” Biochemical Pharmacology, vol. 22, pp. 3099-3108(1973).

[0077] The K_(i) values calculated according to the Cheng-Prassoffequation are provided in the table below: TABLE Norepinephrine SerotoninSelectivity of Reuptake Reuptake K_(i) of Serotonin/ Compound (K_(i) nM)(K_(i) nM) Norepinphrine (S.S) Reboxetine 0.23 ± 0.06 2937 ± 246 12.770(R.R) 7.0 ± 1.7 104 ± 43 15 Reboxetine Reboxetine 1.6 ± 0.6 129 ± 13 81

[0078] The data shows that (S,S) reboxetine is about five to about eightfold more potent than the reboxetine racemate A with respect toinhibiting the reuptake of norepinephrine. In addition, racemicreboxetine has an 81 fold selectivity favoring norepinephrine reuptakeinhibition over serontonin reuptake inhibition. Unexpectedly, theenantiomeric selectivity of the (S,S) and (R,R) reboxetine stereoisomerswith respect to inhibiting the reuptake of norepinephrine and serotoninare quite different. The (S,S) enantiomer is very poor with respect toinhibiting reuptake of serotonin (i.e., a high K_(i)) and, therefore,has a surprisingly high selectivity for the norepinephrine reuptakesite. In particular, the selectivity of serotonin versus norepinephrineincreases from 81 (for the racemate) to 12,770 for an optically pure(S,S) reboxetine. Accordingly, administration of a therapeutic dose of(S,S) reboxetine effectively inhibits nonepinephrine reuptake, butserotonin reuptake essentially is not affected. Likewise, there is afurther increase in separation between the action on norepinephrinereuptake sites and at other receptors. As a consequence, adverse sideeffects associated with the inhibition of serotonin-reuptake andblockade at other receptors are not manifested.

[0079] Surprisingly, this effect is not observed with (R,R) reboxetine,but are quite to the contrary. (R,R) reboxetine is a weaker inhibitorthan (S,S) reboxetine with respect to nonepinphrine reuptake, i.e.,affinity (K_(i)) for (R,R) reboxetine is 7 nM whereas the K_(i) for(S,S) reboxetine is 0.23 nM. In addition, (R,R) reboxetine is much moreeffective at inhibiting serotonin uptake than (S,S) reboxetine, i.e.,K_(i) for (R,R) reboxetine is 104 nM, whereas the K_(i) for (S,S)reboxetine is 2937 nM. Accordingly, (R,R) reboxetine has a lowselectivity for nonepinephrine reuptake inhibition versus serotoninreuptake inhibition.

[0080] The surprisingly high potency of the (S,S) enantiomer over boththe racemic reboxetine and (R,R) reboxetine provides a treatingphysician an ability to prescribe an effective dosage of anorepinephrine reuptake inhibitor, i.e., (S,S) reboxetine, that is about10% to about 20% of the current daily dosage of reboxetine (racemate) toachieve the same reuptake inhibition at the norepinephrine site. Inaddition, the surprisingly high inhibition selectivity of an opticallypure (S,S) reboxetine essentially limits inhibition to norepinephrinereuptake, thereby reducing adverse side effects associated withinhibition at serotonin reuptake sites and blockade at other receptors.

[0081] The foregoing description is given for clearness of understandingonly, and no unnecessary limitations should be understood therefrom, asmodifications within the scope of the invention may be apparent to thosehaving ordinary skill in the art.

What is claimed is:
 1. A method of selectively inhibiting reuptake ofnorepinephrine, the method comprising the step of administering atherapeutically effective amount of a composition to an individual, thecomposition comprising a compound having a pharmacological selectivityof serotonin (K_(i))/norepinephrine (K_(i)) of at least about
 5000. 2.The method of claim 1 wherein said composition, is administered in anamount of about 0.1 to about 10 mg/day.
 3. The method of claim 2 whereinsaid composition is administered in an amount of about 0.5 to about 8mg/day.
 4. The method of claim 3 wherein said composition isadministered in an amount of about 0.5 to about 5 mg/day.
 5. The methodof claim 4 wherein said composition is administered in an amount ofabout 0.5 to about 2.5 mg/day.
 6. The method of claim 5 wherein saidcomposition is administered in an amount of about 0.5 to about 0.9mg/day.
 7. The method of claim 6 wherein said composition isadministered in an amount of about 0.5 to about 0.8 mg/day.
 8. Themethod of claim 7 wherein said composition is administered in an amountof about 0.5 to about 0.75 mg/day.
 9. The method of claim 1 wherein saidcomposition is administered orally, topically, parenterally,transdermally, rectally-, or vaginally.
 10. The method of claim 9wherein said composition is orally administered, and further comprisinga pharmaceutically acceptable carrier selected from the group consistingof a binder, diluent, lubricant, disintegrating agent, effervescingagent, dyestuff, sweetener, wetting agent, and mixtures thereof.
 11. Themethod of claim 10 wherein the oral administration is by a sachet,capsule, tablet, or aerosol spray.
 12. The method of claim 9 whereinsaid composition is parenterally administered subcutaneously,intraveously, or intramuscularly.
 13. The method of claim 1 wherein saidcompound comprises an optically pure (S,S) reboxetine, or apharmaceutically acceptable salt thereof, said compound beingsubstantially free of (R,R) reboxetine.
 14. The method of claim 13wherein the pharmaceutically acceptable salt is a methanesulfonate salt.15. The method of claim 13 wherein the optically pure (S,S) reboxetineor pharmaceutically acceptable salt thereof comprises at least about 90wt. % of (S,S) reboxetine, and less than about 10 wt. % of (R,R)reboxetine, based on the total weight of the (S,S) and (R,R) reboxetinepresent.
 16. The method of claim 15 wherein the optically pure (S,S)reboxetine or pharmaceutically acceptable salt thereof comprises atleast about 97 wt. % of (S,S) reboxetine and less than about 3 wt. % of(R,R) reboxetine, based on the total weight of the (S,S) and (R,R)reboxetine present.
 17. The method of claim 16 wherein the opticallypure (S,S) reboxetine or pharmaceutically acceptable salt thereofcomprises at least about 99 wt. % of (S,S) reboxetine and less thanabout 1 wt. % of (R,R) reboxetine, based on the total weight of the(S,S) and (R,R) reboxetine present.
 18. The method of claim 1 whereinsaid condition is selected from the group consisting of at least one ofan addictive disorder and withdrawal syndrome, an adjustment disorder,an age-associated learning and mental disorder, anorexia nervosa,apathy, an attention-deficit disorder due to general medical conditions,attention-deficit hyperactivity disorder, bipolar disorder, bulimianervosa, chronic fatigue syndrome, chronic or acute stress, chronicpain, conduct disorder, cyclothymic disorder, depression, dysthymicdisorder, fibromyalgia and other somatoform disorders, generalizedanxiety disorder, incontinence, an inhalation disorder, an intoxicationdisorder, mania, migraine headaches, obesity, obsessive compulsivedisorders and related spectrum disorders, oppositional defiant disorder,panic disorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder, a psychotic disorder, seasonalaffective disorder, a sleep disorder, social phobia, a specificdevelopmental disorder, selective serotonin reuptake inhibition (SSRI)“poop out” syndrome, and TIC disorders.
 19. The method of claim 18wherein the addictive disorder comprises an addiction to at least one ofalcohol, nicotine, and other psychoactive substance.
 20. The method ofclaim 18 wherein the adjustment disorder comprises depressed mood,anxiety, mixed anxiety and depressed mood, disturbance of conduct, ormixed disturbance of conduct or mood.
 21. The method of claim 18 whereinthe age-associated learning and mental disorder comprises Alzheimer'sdisease.
 22. The method of claim 18 wherein the depression comprisesadolescent depression or minor depression.
 23. The method of claim 18wherein the premenstrual dysphoric disorder comprises premenstrualsyndrome or late luteal phase dysphoric disorder.
 24. The method ofclaim 18 wherein the psychotic disorder comprises schizophrenia,schizoaffective, or a schizophreniform disorder.
 25. The method of claim18 wherein social phobia comprises social anxiety disorder.
 26. Themethod of claim 18 wherein the sleep disorder comprises narcolepsy orenuresis.
 27. The method of claim 18 wherein somatoform disorderscomprise somatization disorder, conversion disorder, pain disorder,hypochondriasis, body dysmorphic disorder, undifferentiated somatoformdisorder, or somatoform NOS.
 28. The method of claim 18 whereinincontinence comprises stress incontinence, genuine stress incontinence,or mixed incontinence.
 29. The method of claim 18 wherein TIC disorderscomprise Tourette's Disease.
 30. The method of claim 18 wherein saidcondition is selected from the group consisting of at least one of anadjustment disorder, an age-associated learning or mental disorder,apathy, attention-deficit hyperactivity disorder, attention-deficitdisorder caused by medical conditions, bulimia nervosa, chronic fatiguesyndrome, chronic or acute stress, chronic pain, cyclothymic disorder,depression, dysthymic disorder, generalized anxiety disorder, nicotineaddiction, post-traumatic stress disorder, premenstrual dysphoricdisorder, a psychotic disorder, and SSRI “poop out” syndrome.
 31. Themethod of claim 30 wherein said condition is selected from the groupconsisting of at least one of apathy, attention-deficit hyperactivitydisorder, attention-deficit disorder caused by medical conditions,chronic fatigue, cyclothymic disorder, depression, nicotine addiction,post-traumatic stress disorder, and SSRI “poop out” syndrome.
 32. Themethod of claim 1 wherein the compound has a pharmacological selectivityof serotonin (K_(i))/norepinephrine (K_(i)) of at least about 10,000.33. The method of claim 32 wherein the compound has a pharmacologicalselectivity of serotonin (K_(i))/norepinephrine (K_(i)) of at leastabout 12,000.
 34. The method of claim 33 wherein the compound has apharmacological selectivity of serotonin (K_(i))/norepinephrine (K_(i))of at least about 25,000.
 35. The method of claim 34 wherein thecompound has a pharmacological selectivity of serotonin(K_(i))norepinephrine (K_(i)) of at least about 50,000.
 36. The methodof claim 35 wherein the compound has a pharmacological selectivity ofserotonin (K_(i))norepinephrine (K_(i)) of at least about 75,000. 37.The method of claim 36 wherein the compound has a pharmacologicalselectivity of serotonin (K_(i))/norepinephrine (K_(i)) of at leastabout 100,000.
 38. A method of treating a human suffering from acondition, or preventing said condition, wherein inhibiting reuptake ofnorepinephrine provides a benefit, the method comprising the step ofadministering a therapeutically effective amount of a compositioncomprising a compound having a pharmacological selectivity of serotonin(K_(i))/norepinephrine (K_(i)) of at least
 5000. 39. A method oftreating a human suffering from a condition, or preventing saidcondition, wherein inhibiting reuptake of norepinephrine provides abenefit, while diminishing adverse side effects, the method comprisingthe step of administering a total dose of about 0.1 to about 10 mg/dayof an optically pure (S,S) reboxetine, or a pharmaceutically acceptablesalt thereof, to an individual, said optically pure (S,S) reboxetinebeing substantially free of (R,R) reboxetine.
 40. The method of claim 39wherein said adverse side effects comprise dizziness, insomnia,lightheadedness, changes in blood pressure, sweating, gastrointestinaldisturbances, sexual dysfunction in males, anticholinergic-like effects,and side effects with drug-drug interactions.
 41. A method of treatingor preventing a nervous system disorder comprising the step ofadministering a therapeutically effective dose of racemic reboxetine ora pharmaceutically acceptable salt thereof to an individual, whereinsaid disorder is selected from the group consisting of at least one ofan adjustment disorder, an age-associated learning and mental disorder,anorexia nervosa, apathy, an attention-deficit disorder due to generalmedical conditions, bipolar disorder, bulimia nervosa, chronic fatiguesyndrome, chronic or acute stress, chronic pain, cyclothymic disorder,dysthymic disorder, fibromyalgia and other somatoform disorders,incontinence, mania, migraine headaches, obesity, peripheral neuropathy,post-traumatic stress disorder, premenstrual dysphoric disorder, apsychotic disorder, seasonal affective disorder, a sleep disorders, aspecific developmental disorders, SSRI “poop out” syndrome, and TICdisorders.
 42. The method of claim 41 wherein said disorder is selectedfrom the group consisting of at least one of an adjustment disorder, anage-associated learning or mental disorder, apathy, bulimia nervosa,chronic fatigue syndrome, chronic or acute stress, cyclothymic disorder,dysthymic disorder, post-traumatic stress disorder, premenstrualdysphoric disorder, a psychotic disorder, and SSRI “poop out” syndrome.43. The method of claim 42 wherein said disorder is selected from thegroup consisting of at least one of apathy, chronic fatigue syndrome,chronic or acute stress, cyclothymic disorder, post-traumatic stressdisorder, and SSRI “poop out” syndrome
 44. The method of claim 41wherein the reboxetine is administered to the individual in an amount ofabout 2 to about 20 mg/day.
 45. The method of claim 44 wherein thereboxetine is administered to the individual in an amount of about 4 toabout 10 mg/day.
 46. The method of claim 45 wherein the reboxetine isadministered to the individual in an amount of about 6 to about 10 mgday.
 47. The method of claim 41 wherein said reboxetine is administeredorally, parenterally, topically, transdermally, rectally, or vaginally.48. The method of claim 47 wherein said reboxetine is orallyadministered with a pharmaceutically acceptable carrier comprising atleast one of a binder, diluent, lubricant, disintegrating agent,effervescing agent, dyestuff, sweetener, and wetting agent.
 49. Themethod of claim 48 wherein the oral administration is by a sachet,capsule, tablet, or aerosol spray.
 50. The method of claim 47 whereinsaid reboxetine is parentarally administered subcutaneously,intraveously, or intramuscularly.
 51. The method of claim 41 wherein thepharmaceutically acceptable salt is methanesulfonate salt.
 52. Apreparation of a medicament from a composition comprising a compoundhaving a pharmacological selectivity of serotonin (K_(i))norepinephrine(K_(i)) of at least about 5000 to treat or prevent at least one nervoussystem condition selected from the group consisting of an addictivedisorder and withdrawal syndrome, an adjustment disorder, anage-associated learning and mental disorder, anorexia nervosa, apathy,an attention-deficit disorder due to general medical conditions,attention-deficit hyperactivity disorder, bipolar disorder, bulimianervosa, chronic fatigue syndrome, chronic or acute stress, chronicpain, conduct disorder, cyclothymic disorder, depression, dysthymicdisorder, fibromyalgia and other somatoform disorders, generalizedanxiety disorder, incontinence, an inhalation disorder, an intoxicationdisorder, mania, migraine headaches, obesity, obsessive compulsivedisorders and related spectrum disorders, oppositional defiant disorder,panic disorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder, a psychotic disorder, seasonalaffective disorder, a sleep disorder, social phobia, a specificdevelopmental disorder, selective serotonin reuptake inhibition (SSRI)“poop out” syndrome, and TIC disorders.
 53. A preparation of amedicament from a composition comprising racemic reboxetine to treat orprevent at least one nervous system disorder selected from the groupconsisting of an adjustment disorder, an age-associated learning andmental disorder, anorexia nervosa, apathy, an attention-deficit disorderdue to general medical conditions, bipolar disorder, bulimia nervosa,chronic fatigue syndrome, chronic or acute stress, chronic pain,cyclothymic disorder, dysthymic disorder, fibromyalgia and othersomatoform disorders, incontinence, mania, migraine headaches, obesity,peripheral neuropathy, post-traumatic stress disorder, premenstrualdysphoric disorder, a psychotic disorder, seasonal affective disorder, asleep disorders, a specific developmental disorders, SSRI “poop out”syndrome, and TIC disorders.